Summary: Specific combinations of gut microorganisms can worsen symptoms of multiple sclerosis in a mouse model of the autoimmune disease.
Source: RIKEN
Researchers at the RIKEN Center for Integrative Medical Sciences (IMS) report that a particular combination of gut bacteria exacerbates disease symptoms in a mouse model of multiple sclerosis. Published in the journal Nature, the study demonstrates that two distinct gut microbes together enhance the activity of autoreactive immune cells that attack the brain and spinal cord.
Multiple sclerosis is an autoimmune disorder in which the immune system attacks the myelin sheath that insulates nerve fibers in the brain and spinal cord. Loss of myelin disrupts nerve signaling and causes symptoms such as numbness, muscle weakness, tremors, and progressive mobility impairment. Previous research has linked gut microbiota to multiple sclerosis, but the mechanisms by which intestinal bacteria influence inflammation and demyelination in the central nervous system have been unclear.
The RIKEN team, led by Hiroshi Ohno, investigated this gut–brain connection using experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. In this model, demyelination is driven by T cells that produce the inflammatory cytokine IL‑17A. The researchers observed that treating these mice with the antibiotic ampicillin markedly reduced demyelination and prevented activation of a particular population of autoreactive T cells. As Ohno explains, “we found that treatment with ampicillin, and only ampicillin, selectively reduced activity of T cells that attack an important protein called myelin oligodendrocyte glycoprotein (MOG), which helps myelin adhere to neurons.”
To pinpoint where these autoreactive T cells were being primed, the team isolated immune cells from different regions of the intestine and stimulated them with MOG. Only T cells taken from the small intestine showed reduced cytokine production after ampicillin treatment, indicating that microbes in the small intestine were responsible for activating MOG-specific T cells that can later infiltrate and damage the spinal cord. The next objective was to identify the bacterial species involved.
Because only ampicillin—and not other antibiotics—reduced disease severity in the model, the researchers searched for bacterial taxa that were nearly eliminated exclusively by ampicillin. They identified a previously uncharacterized strain they designated OTU002. To test its role, they colonized germ-free mice with only OTU002 and found that these mice developed more severe EAE than germ-free controls, demonstrating that OTU002 contributes to disease exacerbation.
“However, symptoms in mice colonized only with OTU002 were not as severe as those in conventionally colonized model mice,” says first author Eiji Miyauchi. This observation suggested that OTU002 alone could not fully explain the original effect and raised the possibility that a second microbe acts together with OTU002. The team hypothesized that another bacterium might express a peptide that mimics a region of MOG, thereby cross‑reacting with MOG‑specific T cells.
Shotgun genome sequencing of small intestine contents identified a strain of Lactobacillus reuteri that encodes a protein with a sequence resembling part of MOG. Functional assays showed that a peptide from this L. reuteri protein weakly activated MOG‑specific T cells. Crucially, mice co‑colonized with both OTU002 and L. reuteri developed EAE that was significantly worse than in mice colonized with either microbe alone; disease severity in the co‑colonized animals matched that of the original conventionally colonized model. These results demonstrate a synergistic interaction between two gut microbes—one acting as an adjuvant to boost T helper 17 responses and the other providing a molecular mimic that triggers autoreactive T cells.
Miyauchi notes that most prior studies have focused either on fecal communities or on single bacterial species in patients and animal models. The current findings emphasize the importance of considering combined, synergistic effects of intestinal microbes when evaluating autoimmune disease pathogenesis and when developing potential microbiome‑directed therapies for multiple sclerosis.
The authors also caution that differences exist between mouse and human gut microbiota and between mouse and human MOG‑binding T cell specificities. Accordingly, further studies using human-derived microbes and autoreactive human T cells will be needed to determine whether similar microbial interactions influence multiple sclerosis in people.
About this multiple sclerosis research article
Source:
RIKEN
Contacts:
Adam Phillips – RIKEN
Image Source:
The image is in the public domain.
Original Research:
Closed access. DOI reference: 10.1038/s41586-020-2634-9. Article title: “Gut microorganisms act together to exacerbate inflammation in spinal cords” by Eiji Miyauchi et al., published in Nature.
Abstract
Gut microorganisms act together to exacerbate inflammation in spinal cords
Evidence increasingly supports a pathogenic role for gut microorganisms in autoimmune diseases such as multiple sclerosis. Studies using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, alongside human studies, have implicated the intestinal microbiota in disease onset and severity. Yet the mechanisms by which gut microbes influence inflammation in distant tissues such as the spinal cord remain unclear. This study shows that two distinct microbial signals from the small intestine work together to activate autoreactive CD4+ T cells that specifically recognize myelin oligodendrocyte glycoprotein (MOG). After EAE induction, MOG‑specific CD4+ T cells appear in the small intestine. Monocolonization of germ‑free mice demonstrated that a newly isolated strain in the Erysipelotrichaceae family functions like an adjuvant to enhance T helper 17 responses, while a Lactobacillus reuteri strain encodes peptides that can mimic MOG. Mice co‑colonized with both strains developed more severe EAE than germ‑free or monocolonized mice. These results indicate that synergistic interactions among gut microorganisms can promote autoimmune inflammation of the spinal cord and suggest that targeting such microbial interactions could inform preventive or therapeutic strategies for multiple sclerosis.